The invention relates to compounds which are intended to be used in the pharmaceutical industry as active compounds for the production of medicaments.
1. Prior Art
International Patent Applications WO 94/13290, 94/19346, 95/01351, 95/15324, 96/00224, 95/34554, 95/34553, 96/02534 and 96/02505 describe benzimidazole and imidazopyridine derivatives which are said to be suitable for the control of Helicobacter bacteria.
2. Description of the Invention
The invention relates to compounds of the formula I 
in which
R1, R2 and R3 are identical to or different from one another and are hydrogen, 1-4C-alkyl, 1-4C-alkoxy, hydroxyl, halogen, carboxyl or 1-4C-alkylthio,
R4 is hydrogen or 1-4C-alkyl,
R5 is hydrogen or 1-4C-alkyl,
R6 is hydrogen or 1-4C-alkyl,
R7 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,
R8 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen,
R9 is hydrogen or 14C-alkyl,
A is 1-7C-alkylene, 2-7C-alkenylene, 3-7C-cycloalkylene or phenylene,
G is hydrogen, 1-7C-alkyl, 1-4C-alkyl which is completely or mainly substituted by fluorine, 2-7C-alkenyl, 3-7C-cycloalkyl, a mono- or di-1-4C-alkylcarbamoyl or -thiocarbamoyl radical, an N-1-4C-alkyl-Nxe2x80x2-cyanoamidino radical, a 1-N-1-4C-alkylamino-2-nitroethylene radical, an N-2-propynyl-Nxe2x80x2-cyanoamidino radical, an aminosulfonylamidino radical, the radical xe2x80x94N(R10)R11, the part of the compound of the above formula I bonded to A (including X and via X) or a cyclic system or bicyclic system which is unsubstituted or substituted by R12 and R13 and which is selected from the group consisting of benzene, naphthalene, furan, thiophene, pyrrole, oxazole, oxazoline, oxazolidinone, isoxazole, thiazole, thiazoline, isothiazole, imidazole, imidazoline, pyrazole, triazole, tetrazole, thiadiazole, thiadiazole 1-oxide, oxadiazole, pyridine, pyridine N-oxide, pyrimidine, halopyrimidine, piperidine, triazine, pyridone, benzimidazole, imidazopyridine, benzothiazole, benzoxazole, quinoline and imidazopyridazine,
in which
R10 is 1-7C-alkyl, 3-7C-cycloalkyl or Ar-1-4C-alkyl and
R11 is 1-7C-alkyl, 3-7C-cycloalkyl or Ar-1-4C-alkyl,
where
Ar is phenyl, furyl, naphthyl, tetrahydronaphthyl or phenyl which is substituted by R14, R15 and R16,
or in which
R10 and R 11, together and including the nitrogen atom to which both are bonded, are an unsubstituted or substituted 5- or 6-membered ring hetero(bi)cyclic system which is selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, indoline, 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline,
xe2x80x83where
a substituted pyrrolidino radical is substituted by one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, hydroxy-1-4C-alkyl, hydroxyl and carboxyl,
a substituted piperidino radical is substituted by one, two or three identical or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, phenyl or phenyl-1-4C-alkyl, which is substituted by R14, R15 and R16, benzoyl, benzoyl substituted by halogen and carboxyl,
a substituted piperazino radical can be substituted in the 2-, 3-, 5- or 6-position by a 1-4C-alkyl radical, and is substituted in the 4-position by a substituent selected from the group consisting of 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl and carbamoyl,
a substituted morpholino radical is substituted by one or two identical or different 1-4C-alkyl radicals,
a substituted thiomorpholino radical is substituted by one or two identical or different 1-4C-alkyl radicals or a carboxyl group,
a substituted indolin-1-yl radical can be substituted in the 2- and/or 3-position by a carboxyl group or by one or two identical or different 1-4C-alkyl radicals, and can be substituted in the benzo moiety by one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, halogen and nitro,
a substituted 1,2,3,4-tetrahydroquinoline radical is substituted by one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl and halogen,
a substituted 1,2,3,4-tetrahydroisoquinoline radical is substituted by one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, carboxyl and phenyl,
R12 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxy, halogen, nitro, guanidino, carboxyl, 1-4C-alkoxycarbonyl, 1-4C-alkyl substituted by R17, phenyl substituted by R14, R15 and R16 or xe2x80x94N(R18)R19,
R13 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxy, halogen or trifluoromethyl,
R14 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxy, 1-4C-alkylcarbonyl, halogen, trifluoromethyl, 1-4C-alkylamino or nitro,
R15 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxy, halogen or nitro, and
R16 is hydrogen or trifluoromethyl,
R17 is hydroxyl, 3-7C-cycloalkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, pyridinyl or xe2x80x94N(R18)R19,
where
R18 is hydrogen, 1-4C-alkyl or xe2x80x94COxe2x80x94R20 and
R19 is hydrogen or 1-4C-alkyl,
or where
R18 and R19, together and including the nitrogen atom to which both are bonded, are a piperidino or morpholino radical,
R20 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
X is O (oxygen), N-1-4C-alkyl, NH or S,
Y is O (oxygen), N-1-4C-alkyl, NH, S, 1,4-piperazinylene or 1,4-piperidinylene,
Z is O (oxygen), N-1-4C-alkyl, NH or S or CO,
m is a number from 1 to 7,
n is a number from 0 to 4,
t is the number 0 or 1 and
u is the number 0 or 1,
and their salts.
1-4C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
1-4C-Alkoxy represents a radical which, in addition to the oxygen atom, contains one of the abovementioned 1-4C-alkyl radicals. Examples which may be mentioned are the methoxy and the ethoxy radicals.
Halogen within the meaning of the present invention is bromine, chlorine or fluorine.
1-4C-Alkylthio represents a radical which, in addition to the sulfur atom, contains one of the abovementioned 1-4C-alkyl radicals. Examples which may be mentioned are the methylthio and the ethylthio radicals.
1-7C-Alkylene represents straight-chain or branched 1-7C-alkylene radicals, for example the methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94), trimethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94), tetra-methylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94), 1,2-dimethylethylene [xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94], 1,1-dimethylethylene [xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94], 2,2-dimethylethylene [xe2x80x94CH2xe2x80x94C(CH3)2xe2x80x94], isopropylidene [xe2x80x94C(CH3)2xe2x80x94], 1-methylethylene [xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94], pentamethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94), hexamethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94) and the heptamethylene (xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94) radicals. When t is the number 1 or t is the number 0 and at the same time u is the number 1, A preferably has the meaning 2-7C-alkylene. Of the alkylene radicals A, the ethylene, the propylene and the butylene radicals are preferred.
2-7C-Alkenylene represents straight-chain or branched 2-7C-alkenylene radicals, under which is understood a mono- or polyunsaturated divalent hydrocarbon radical. Examples which may be mentioned are the vinylene (xe2x80x94CHxe2x95x90CHxe2x80x94), 1-propenylene (xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94), 2-butenylene (xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94) and the 1,3-butadienylene (xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94) radicals.
3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
3-7C-Cycloalkylene represents one of the abovementioned 3-7C-cycloalkyl radicals having two bonds. An example which may be mentioned is the 1,4-cyclohexylene radical.
Phenylene represents the 1,2-, 1,3- and 1,4-phenylene radicals, of which the 1,4-phenylene radical is preferred.
1-7C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl, (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl-(3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
Examples of 1-4C-alkyl which is completely or mainly substituted by fluorine are the 2,2,3,3,3-pentafluoropropyl, the perfluoroethyl and the 1,2,2-trifluoroethyl radicals, in particular the 1,1,2,2-tetrafluoroethyl, the 2,2,2-trifluoroethyl, the trifluoromethyl and the difluoromethyl radicals.
2-7C-Alkenyl represents straight-chain or branched alkenyl radicals having 2 to 7 carbon atoms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl, 2-propenyl (allyl) and vinyl radicals.
Mono- or di-1-4C-alkylcarbamoyl radicals are carbamoyl radicals (xe2x80x94COxe2x80x94NH2) which are substituted by one or two identical or different 1-4C-alkyl radicals from those mentioned above. Examples which may be mentioned are the methylcarbamoyl, the isopropylcarbamoyl and the dimethylcarbamoyl radicals.
Mono- or di-1-4C-alkylthiocarbamoyl radicals are thiocarbamoyl radicals (xe2x80x94CSxe2x80x94NH2) which are substituted by one or two identical or different 1-4C-alkyl radicals from those mentioned above. Examples which may be mentioned are the methylthiocarbamoyl, the isopropylthiocarbamoyl and the dimethylthiocarbamoyl radicals.
An example of an N-1-4C-alkyl-Nxe2x80x2-cyanoamidino radical which may be mentioned is in particular the N-methyl-Nxe2x80x2-cyanoamidino radical [xe2x80x94C(xe2x95x90NCN)xe2x80x94NHxe2x80x94CH3].
An example of a 1-N-1-4C-alkylamino-2-nitroethylene radical which may be mentioned is in particular the 1-N-methylamino-2-nitroethylene radical [xe2x80x94C(NHCH3)xe2x95x90CHNO2].
Exemplary radicals xe2x80x94[Zxe2x80x94CnH2n]uxe2x80x94G where G=an N-1-4C-alkyl-Nxe2x80x2-cyanoamidino radical, 1-N-1-4C-alkylamino-2-nitroethyl radical or N-2-propynyl-Nxe2x80x2-cyanoamidino radical to be mentioned are in particular those radicals in which Z has the meaning NH and n is the number 0. In this connection, radicals xe2x80x94[Zxe2x80x94CnH2n]uxe2x80x94G particularly to be mentioned are the radicals xe2x80x94NHxe2x80x94C(xe2x95x90NCN)NHxe2x80x94CH3, xe2x80x94NHxe2x80x94C(NHCH3)xe2x95x90CHNO2 and xe2x80x94NHxe2x80x94C(xe2x95x90NCN)NHxe2x80x94CH2Cxe2x95x90CH.
1-4C-Alkoxy-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxy radicals. Examples which may be mentioned are the methoxymethyl radical, the methoxyethyl radical and the butoxyethyl radical.
1-4C-Alkoxycarbonyl represents a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl (CH3Oxe2x80x94C(O)xe2x80x94) and the ethoxycarbonyl (CH3CH2Oxe2x80x94C(O)xe2x80x94) radicals.
In addition to the oxygen atom, 1-4C-alkoxycarbonyloxy radicals contain one of the abovementioned 1-4C-alkylcarbonyl radicals. An example which may be mentioned is the acetoxy radical (CH3COxe2x80x94Oxe2x80x94).
Hydroxy-1-4C-alkyl represents abovementioned 1-4C-alkyl radicals which are substituted by a hydroxyl group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl radicals.
3-7C-Cycloalkyl-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl radicals.
1-4C-Alkoxycarbonyl-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned 1-4C-alkoxycarbonyl radicals. An example which may be mentioned is the ethoxycarbonylmethyl radical (CH3CH2OC(O)CH2xe2x80x94).
Phenyl-1-4C-alkyl represents one of the abovementioned 1-4C-alkyl radicals which is substituted by phenyl. Examples which may be mentioned are the phenethyl and the benzyl radicals.
Exemplary 1-4C-alkyl radicals substituted by R17 which may be mentioned are the 2-methoxycarbonylethyl, the 2-ethoxycarbonylethyl, the methoxycarbonylmethyl, the carboxymethyl, the 2-hydroxyethyl, the methoxymethyl, the 2-methoxyethyl, the 2-hydroxyethyl, the dimethylaminomethyl and the 2-dimethylaminoethyl radicals and, in particular, the cyclopropylmethyl and the pyridin4-ylmethyl radicals.
Possible radicals xe2x80x94CmH2mxe2x80x94 are straight-chain or branched radicals. Examples which may be mentioned are the heptylene, isoheptylene (2-methylhexylene), hexylene, isohexylene (2-methylpentylene), neohexylene (2,2-dimethylbutylene), pentylene, isopentylene (3-methylbutylene), neopentylene (2,2-dimethylpropylene), butylene, isobutylene, sec-butylene, tert-butylene, propylene, isopropylene, ethylene and methylene radicals. Radicals xe2x80x94CmH2mxe2x80x94 preferably to be mentioned are the methylene (xe2x80x94CH2xe2x80x94), the ethylene (xe2x80x94CH2CH2xe2x80x94), the butylene (xe2x80x94CH2CH2CH2CH2xe2x80x94) and the propylene (xe2x80x94CH2CH2CH2xe2x80x94) radicals.
Possible radicals xe2x80x94CnH2nxe2x80x94 are likewise straight-chain or branched radicals. Examples which may be mentioned are the butylene, iso-butylene, sec-butylene, tert-butylene, propylene, isopropylene, ethylene and methylene radicals. Radicals xe2x80x94CnH2nxe2x80x94 preferably to be mentioned are the methylene (xe2x80x94CH2xe2x80x94) and ethylene (xe2x80x94CH2CH2xe2x80x94) radicals.
In one embodiment, n is the number 0 so that (with the condition that u is the number 1) the expression xe2x80x94CnH2nxe2x80x94 is a bonding dash and the radical G is bonded directly to the group Z. This embodiment relates to those compounds in which G is hydrogen or a radical which is bonded to Z via a carbon atom.
In a further embodiment t is the number 0, so that the expression Yxe2x80x94CmH2m is a bonding dash.
In a further embodiment u is the number 0, so that the expression Zxe2x80x94CnH2n is a bonding dash.
The person skilled in the art is aware on account of his/her expert knowledge that certain combinations and conformations of X, A, Y, Z, G, m, n, t and u would lead to chemically less stable compounds. This applies in particular to those compounds in which two hetero-atoms (S, O or N) would directly meet or would only be separated by one carbon atom. Those compounds according to the invention which do not have the abovementioned conformations are therefore preferred.
The substituents R12 and R13 can be bonded to the cyclic systems or bicyclic systems G in any conceivable position, it being possible for the substituted or unsubstituted cyclic systems or bicyclic systems G themselves to be linked to the remainder of the molecule in any conceivable position. Exemplary radicals G which may be mentioned which are unsubstituted or substituted by R12 and R13 are: phenyl, 4-methylphenyl, 3-dimethylaminomethylphenyl, 3-piperidinomethylphenyl, 3-carboxymethylphenyl, 2-dimethylaminomethyl-5-methyl-3-furyl, pyrrol-1-yl, 1-methylpyrrol-3-yl, 4,5-dimethyloxazol-2-yl, 3,5-dimethylisoxazol-4-yl, 4,5-dimethylthiazol-2-yl, 4-methyl-5-carboxymethylthiazol-2-yl, 1-methylimidazol-2-yl, 1-methylpyrazol-3-yl, 1-(2-dimethylaminoethyl)pyrazol-3-yl, 5-methyl-1,3,4-oxa diazol-2-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-2-yl, 1-methyl-1,2,3-triazol-4-yl, 1-methyl-1,2,4-triazol-3-yl, 1-(2-dimethylaminoethyl)-1,2,3-triazol-4-yl, 1-methyltetrazol-5-yl, 1-(2-dimethylaminoethyl)tetrazol-5-yl, 1-carboxymethyltetrazol-5-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl 1-(2-hydroxyethyl)tetrazol-5-yl, 2-amino-1 ,3,4-thiadiazol-2-yl, 3-amino-1,2,4-triazol-5-yl, 4-methyl-5-trifluoromethyl-1,2,4-triazol-3-yl, 4-aminopyrimidin-2-yl, 2-furyl, 3-furyl, 3-methyl-2-furyl, 2-methyl-3-furyl, 5-methyl-2-furyl, 5-ethyl-2-furyl, 3-methoxy-2-furyl, 5-dimethylaminomethyl-2-furyl, 5-N-morpholinomethyl-2-furyl, 5-methoxymethyl-2-furyl, 5-hydroxymethyl-2-furyl, 5-N-piperidinomethyl-2-furyl, 5-chloro-2-furyl, 5-fluoro-2-furyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 5-chloro-2-thienyl, 3-methyl-2-thienyl, 3-amino-2-thienyl, 3-guanidino-2-thienyl, 3-methoxy-2-thienyl, 2-methyl-3-thienyl, 5-dimethylaminomethyl-2-thienyl, 5-N-morpholinomethyl-2-thienyl, 5-methyl-2-pyrrolyl, 2,5-dimethyl-1-pyrrolyl, 1,5-dimethyl-2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-amino-4-thiazolyl, 2-methyl-4-thiazolyl, 2-amino-5-methyl-4-thiazolyl, 4-methyl-5-thiazolyl, 2-dimethylaminomethyl-4-thiazolyl, 2-guanidino-4-thiazolyl, 2-formylamino-4-thiazolyl, 2-N-morpholinomethyl-4-thiazolyl, 4-methyl-5-oxazolyl, 3-guanidino-1-pyrazolyl, 3-guanidino-4-pyrazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-methyl-4-imidazolyl, 5-methyl-4-imidazolyl, 2-methyl-1-imidazolyl, 2-methyl-5-nitro-1- imidazolyl, 4,5-dimethyl-2-imidazolyl, 4-hydroxymethyl-5-methyl-1-imidazolyl, 3-methyl-1-pyrazolyl, 5-amino-1,2,4-thiadiazol-3-yl, 4-methoxy-2-pyridinyl, 4-methoxy-3-methyl-2-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 5-chloro-4-pyrimidinyl, 5-chloro-2,6-dimethyl-4-pyrimidinyl, 2-nitro-1-imidazolyl, 3,4-dimethoxypyridinyl, 1H-benzimidazol-2-yl, 6-imidazof[1,2-b]pyridazinyl and 3-nitro-6-imidazo[1,2-b]-pyridazinyl.
Exemplary phenyl radicals which may be mentioned which are substituted by R14, R15 and R16 are the radicals 3,4-dihydroxy, 3-hydroxy-4-methoxy, 3,4-dimethoxy, 2-methoxy, 2-ethoxy, 3-methoxy, 4-methoxy, 2-hydroxy, 3-hydroxy, 4-hydroxy, 3,4-dihydroxy, 4-acetyl, 4-fluoro, 4-chloro, 2-chloro, 3-chloro, 3,4-dichloro, 3-trifluoromethyl, 2-trifluoromethyl, 2-methyl, 3-methyl, 4-methyl, 2,3-dimethyl, 2,4-dimethyl, 3,4-dimethyl, 2,5-dimethyl, 4-nitro, 2,6-dinitro-4-trifluormethyl and 5-chloro-2-methyl-aminophenyl.
Examples of substituted pyrrolidino radicals which may be mentioned are the 2-methoxymethylpyrrolidino, 2-methoxycarbonylpyrrolidino, 2-methylpyrrolidino, 2,5-dimethylpyrrolidino, 2-carboxypyrrolidino, 4-hydroxy-2-methoxycarbonylpyrrolidino, 4-hydroxy-2-ethoxycarbonylpyrrolidino, 2-(2-hydroxyethyl)pyrrolidino, 4-hydroxy-2-carboxypyrrolidino, 2-hydroxymethylpyrrolidino, 3-hydroxy-pyrrolidino and the 4-acetoxy-2-carboxypyrrolidino radicals.
Examples of substituted piperidino radicals which may be mentioned are the 2-carboxypiperidino, 2-n-propylpiperidino, 5-ethyl-2-methylpiperidino, 4-hydroxymethyl-4-phenylpiperidino, 4-n-propylpiperidino, 4-(3-phenylpropyl)piperidino, 2,6-dimethylpiperidino, 4-phenyl-4-propyloxycarbonylpiperidino, 4-ethoxycarbonyl-4-phenylpiperidino, 4-carboxy4-phenylpiperidino, 4-carboxypiperidino, 4-(4-fluorobenzoyl)piperidino, 4-(4-chlorobenzoyl)piperidino, 2,3-dicarboxypiperidino, 2,4-dicarboxypiperidino, 2,6-dicarboxypiperidino, 2-ethoxycarbonylpiperidino, 2-methylpiperidino, 2,6-dimethylpiperidino, 2-hydroxymethylpiperidino, 2-ethylpiperidino, 2-(2-hydroxyethyl)piperidino, 3-ethoxycarbonylpiperidino and the 4-benzylpiperidino radicals.
Examples of substituted piperazino radicals which may be mentioned are the 4-methylpiperazino, 4-phenylpiperazino, 4-(2-methylphenyl)piperazino, 4-(2,3-dimethylphenyl)piperazino, 4-(2-chlorophenyl)piperazino, 4-(2-methoxyphenyl)piperazino, 4-(2-ethoxyphenyl)piperazino, 4-(3-chlorophenyl)piperazino, 4-(4-fluorophenyl)piperazino, 4-(4-chlorophenyl)piperazino, 4-(4-methoxyphenyl)piperazino, 4-carbamoylpiperazino, 3-methyl-4-(4-chlorophenyl)piperazino, 3-methyl4-(4-methoxyphenyl)piperazino, 3-methyl-4-(4-methylphenyl)piperazino, 4-(2,4-dimethylphenyl)piperazino, 4-(3,4-dichlorophenyl)piperazino, 4-(3,4-dimethylphenyl)piperazino, 3-methyl4-(2,5di-phenylpiperazino, 3-methyl4-(3-chlorophenyl)piperazino, 4-benzylpiperazino, 4-propylpiperazino, 4-(3-methylphenyl)piperazino, 4-(3-methoxyphenyl)piperazino, 4-(4-methylphenyl)piperazino, 4-(2,5-di-methylphenyl)piperazino, 4-cyclopropylpiperazino, 4-cyclobutylpiperazino, 4-cyclopentylpiperazino, 4-cyclohexylpiperazino, 4-cycloheptylpiperazino, 4-n-butylpiperazino, 4-isobutylpiperazino, 4-tert-butylpiperazino, 4-(1 -phenylethyl)piperazino, 4-ethoxycarbonylmethylpiperazino, 4-(2-phenylethyl)piperazino, 4-(2-cyclohexylethyl)piperazino, 4-(2-hydroxyphenyl)piperazino, 4-(3,4-dimethoxyphenyl)piperazino, 4-isopropylpiperazino, 3-methyl4-(3-methoxyphenyl)piperazino, 4-(4-hydroxyphenyl)piperazino, 3-methyl4-(3-methylphenyl)piperazino, 4-(3-hydroxyphenyl)piperazino, 4-(2,6-di-nitro-4-trifluoromethylphenyl)piperazino, 4-(4-nitrophenyl)piperazino, 4-(4-acetylphenyl)piperazino, 4-(2-chloro-5-thienylmethyl)piperazino and the 4-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]piperazino radicals.
An example of a substituted morpholino radical which may be mentioned is the 3,5-dimethylmorpholino radical.
An example of a substituted thiomorpholino radical which may be mentioned is the 2-carboxythiomorpholino radical.
Examples of substituted indolin-1-yl radicals which may be mentioned are the 2-carboxy-1-indolinyl, 6-fluoro-1-indolinyl, 5-bromo-1-indolinyl, 2,7-dimethyl-l-indolinyl, 2-methyl-1-indolinyl, 5-bromo-7-nitro-1-indolinyl, 5-nitro-1 -indolinyl, 2,3-dimethyl-1 -indolinyl and the 6-nitro-l -indolinyl radicals.
Examples of substituted 1,2,3,4-tetrahydroquinoline radicals which may be mentioned are the 2-ethoxycarbonyl-1,2,3,4-tetrahydro-1-quinolinyl, 2-methyl-1,2,3,4-tetrahydro-1-quinolinyl, 6-methyl-1,2,3,4-tetrahydro-1-quinolinyl, 6-fluoro-2-methyl-1,2,3,4-tetrahydro-l-quinolinyl, 4-methyl-1,2,3,4-tetrahydro-1-quinolinyl and the 2-fluoro-6-methyl-1,2,3,4-tetrahydro-1-quinolinyl radicals.
An example of a substituted 1,2,3,4-tetrahydroisoquinoline radical which may be mentioned is the 3-carboxy-1,2,3,4-tetrahydro-2-isoquinolinyl radical.
Exemplary quinolin-3-yl radicalsxe2x80x94with the substituents R1, R2 and R3 in the positions 2, 4, 5, 6, 7 or 8-which may be mentioned with the aid of the xe2x80x9cTable of quinolin-3-yl radicalsxe2x80x9d are the following radicals:
In the above table, Me is CH3 and Et is C2H5.
Suitable salts of compounds of the formula Ixe2x80x94depending on substitutionxe2x80x94are all acid addition salts or all salts with bases. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids and bases customarily used in pharmacy. Those suitable are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids can be employed in salt preparationxe2x80x94depending on whether it is a mono- or polybasic acid and depending on which salt is desiredxe2x80x94in an equimolar quantitative ratio or one differing therefrom.
On the other hand, salts with bases are also suitable. Examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, where here too the bases are employed in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically intolerable salts which can be initially obtained, for example, as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention, as well as their salts, if they are isolated, for example, in crystalline form, can contain various amounts of solvents. The invention therefore also includes all solvates and in particular all hydrates of the compounds of the formula I, and all solvates and in particular all hydrates of the salts of the compounds of the formula I.
One embodiment (embodiment a) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is O (oxygen) and Y is S, t is the number 1 and u is the number 0.
A further embodiment (embodiment b) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is S and Y is S, t is the number 1 and u is the number 0.
A further embodiment (embodiment c) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is S and Y is 1,4-piperazinylene, t is the number 1 and u is the number 0.
A further embodiment (embodiment d) of the invention relates to compounds of the formula I in which A is 1-7C-alkylene, X is S and t and u are the number 0.
A further embodiment (embodiment e) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is S and Z is S, n and t are the number 0 and u is the number 1.
A further embodiment (embodiment f) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is S and Y is 1,4-piperazinylene, t is the number 1 and u is the number 0 and G is the part of the compound of the formula I bonded to A (including S and via S).
A further embodiment (embodiment g) of the invention relates to compounds of the formula I in which A is 1-7C-alkylene, X is O (oxygen) and t and u are the number 0.
A further embodiment (embodiment h) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is O (oxygen) and Y is 1,4-piperazinyl, t is the number 1 and u is the number 0.
A further embodiment (embodiment i) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is S and Z is NH, n and t are the number 0 and u is the number 1.
A further embodiment (embodiment j) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is O (oxygen) and Z is S, n and t are the number 0 and u is the number 1.
A further embodiment (embodiment k) of the invention relates to compounds of the formula I in which A is 1-7C-alkylene, 2-7C-alkenylene, 3-7C-cycloalkylene or phenylene, t and u are the number 0 and G is hydrogen.
A further embodiment (embodiment I) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is N-1-4C-alkyl and Y is S, t is the number 1 and u is the number 0.
A further embodiment (embodiment m) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is S, Y is O (oxygen) and Z is O (oxygen), t and u are the number 1, m is a number from 2 to 7, n is the number 0 and G is 1-4C-alkyl which is completely or mainly substituted by fluorine.
A further embodiment (embodiment n) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is N-1-4C-alkyl and Z is O (oxygen), t and n are the number 0 and u is the number 1.
A further embodiment (embodiment o) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is N-1-4C-alkyl and Z is S, t and n are the number 0 and u is the number 1.
A further embodiment (embodiment p) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is S and Z is O (oxygen), t and n are the number 0 and u is the number 1.
A further embodiment (embodiment q) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is N-1-4C-alkyl and Z is O (oxygen), t and n are the number 0 and u is the number 1 and G is hydrogen.
A further embodiment (embodiment r) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is N-1-4C-alkyl and t and u are the number 0.
A further embodiment (embodiment s) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is S, Y is S, Z is O (oxygen) and t and u are the number 1.
A further embodiment (embodiment t) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is O (oxygen), Y is S, Z is O (oxygen) and t and u are the number 1.
A further embodiment (embodiment u) of the invention relates to compounds of the formula I in which A is 2-7C-alkylene, X is O (oxygen), Y is O (oxygen), Z is S and t and u are the number 1.
Compounds of the embodiments I, n, o, q and r which are particularly worthy of mention are those in which R7 is halogen, in particular chlorine.
Compounds of the embodiments e, i, j, n, o and p which are particularly worthy of mention are those in which G is 3-nitroimidazo[1,2-b]pyridazin-6-yl.
Preferred compounds of the invention are those of the embodiments c, d, e, f, j, m, s, t and u.
Particularly preferred compounds of the invention are those of the embodiments a and b.
One group of compounds according to the invention are those compounds, in which G has the meaning oxazolidinone and/or R17 has the meaning 3-7C-cycloalkyl or pyridinyl.
Another group of compounds according to the invention are those compounds, in which the meaning of G is other than oxazolidinone and the meaning of R17 is other than 3-7C-cycloalkyl and pyridinyl.
Compounds according to the invention to be emphasized are those of the formula I in which
R1, R2 and R3 are identical to or different from one another and are hydrogen or halogen,
R4 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
R7 is hydrogen, 1-4C-alkyl or halogen,
R8 is hydrogen,
R9 is hydrogen,
A is 1-7C-alkylene,
G is hydrogen, 1-4C-alkyl which is completely or mainly substituted by fluorine, the radical xe2x80x94N(R10)R11, the part of the compound of the above formula I bonded to A (including X and via X) or a cyclic system or bicyclic system which is unsubstituted or substituted by R12 and R13 and which is selected from the group consisting of benzene, naphthalene, furan, thiophene, pyrrole, oxazole, oxazoline, oxazolidinone, isoxazole, thiazole, thiazoline, isothiazole, imidazole, imidazoline, pyrazole, triazole, tetrazole, thiadiazole, thiadiazole 1-oxide, oxadiazole, pyridine, pyridine N-oxide, pyrimidine, chloropyrimidine, piperidine, triazine, pyridone, benzimidazole, imidazopyridine, benzothiazole, benzoxazole, quinoline and imidazopyridazine,
in which
R10 and R11, together and including the nitrogen atom to which both are bonded, are an unsubstituted or substituted 5- or 6-membered ring hetero(bi)cyclic system which is selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, indoline, 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline,
xe2x80x83where
a substituted pyrrolidino radical is substituted by one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, hydroxy-1-4C-alkyl, hydroxyl and carboxyl,
a substituted piperidino radical is substituted by one, two or three identical or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, phenyl or phenyl-1-4C-alkyl, which is substituted by R14, R15 and R16, benzoyl, benzoyl substituted by halogen and carboxyl,
a substituted piperazino radical can be substituted in the 2-, 3-, 5- or 6-position by a 1-4C-alkyl radical, and is substituted in the 4-position by a substituent selected from the group consisting of 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl and carbamoyl,
a substituted morpholino radical is substituted by one or two identical or different 1-4C-alkyl radicals,
a substituted thiomorpholino radical is substituted by one or two identical or different 1-4C-alkyl radicals or a carboxyl group,
a substituted indolin-1-yl radical can be substituted in the 2- and/or 3-position by a carboxyl group or by one or two identical or different 1-4C-alkyl radicals, and can be substituted in the benzo moiety by one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, halogen and nitro,
a substituted 1,2,3,4-tetrahydroquinoline radical is substituted by one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxycarbonyl and halogen,
a substituted 1,2,3,4-tetrahydroisoquinoline radical is substituted by one or two identical or different substituents selected from the group consisting of 1-4C-alkyl, carboxyl and phenyl,
R12 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxy, halogen, nitro, guanidino, carboxyl, 1-4C-alkoxycarbonyl, 1-4C-alkyl substituted by R17, phenyl substituted by R14, R15 and R16 or xe2x80x94N(R18)R19,
R13 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxy, halogen or trifluoromethyl, R14 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxy, 1-4C-alkylcarbonyl, halogen, trifluoromethyl, 1-4C-alkylamino or nitro,
R15 is hydrogen, 1-4C-alkyl, hydroxyl, 1-4C-alkoxy, halogen or nitro, and
R16 is hydrogen or trifluoromethyl,
R17 is hydroxyl, 3-7C-cycloalkyl, 1-4C-alkoxy, carboxyl, 1-4C-alkoxycarbonyl, pyridinyl or xe2x80x94N(R18)R19,
where
R18 is hydrogen, 1-4C-alkyl or xe2x80x94COxe2x80x94R20 and
R19 is hydrogen or 1-4C-alkyl,
or where
R18 and R19, together and including the nitrogen atom to which both are bonded, are a piperidino or morpholino radical,
R20 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
X is O (oxygen), N-1-4C-alkyl, NH or S,
Y is O (oxygen), N-1-4C-alkyl, NH, S or 1,4-piperazinylene,
Z is O (oxygen), N-1-4C-alkyl, NH or S,
m is a number from 1 to 7,
n is a number from 0 to 4,
t is the number 0 or 1 and
u is the number 0 or 1,
and their salts.
Compounds according to the invention to be emphasized particularly are those of the formula I in which
R1, R2 and R3 are hydrogen,
R4 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
R7 is 1-4C-alkyl or halogen,
R8 is hydrogen,
R9 is hydrogen,
A is 1-7C-alkylene,
G is hydrogen, 1-4C-alkyl which is completely or mainly substituted by fluorine, the radical xe2x80x94N(R10)R11 or a cyclic system which is unsubstituted or substituted by R12 and R13 and which is selected from the group consisting of benzene, furan, thiophene, oxazole, oxazoline, oxazolidinone, thiazole, imidazole, triazole, tetrazole, pyridine, pyrimidine, chloropyrimidine, piperidine and imidazopyridazine,
in which
R10 and R11, together and including the nitrogen atom to which both are bonded, are an unsubstituted or substituted 5- or 6-membered ring hetero(bi)cyclic system which is selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline,
xe2x80x83where
a substituted piperazino radical is substituted in the 4-position by a substituent selected from the group consisting of 1-4C-alkyl and carbamoyl,
R12 is hydrogen, 1-4C-alkyl, hydroxyl, halogen, nitro, carboxyl, 1-4C-alkoxycarbonyl or 1-4C-alkyl substituted by R17,
R13 is hydrogen or 1-4C-alkyl,
R17 is 3-7C-cycloalkyl or pyridinyl,
X is O (oxygen), N-1-4C-alkyl or S,
Y is O (oxygen), S or 1,4-piperazinylene,
Z is O (oxygen) or S,
m is a number from 1 to 4,
n is a number from 0 to 2,
t is the number 0 or 1 and
u is the number 0 or 1,
and their salts.
Preferred compounds according to the invention are those of the formula I in which
R1, R2 and R3 are hydrogen,
R4 is hydrogen,
R5 is hydrogen,
R6 is hydrogen,
R7 is 1-4C-alkyl
R8 is hydrogen,
R9 is hydrogen,
A is 2-4C-alkylene,
G is hydrogen, 1-4C-alkyl which is completely or mainly substituted by fluorine or a cyclic system which is unsubstituted or substituted by R12 and R13 and which is selected from the group consisting of thiophene, oxazoline, oxazolidinone, imidazole, pyridine, pyrimidine and piperidine
in which
R12 is hydrogen, 1-4C-alkyl, hydroxyl, halogen, nitro or 1-4C-alkyl substituted by R17,
R13 is hydrogen or 1-4C-alkyl,
R17 is 3-7C-cycloalkyl or pyridinyl,
X is O (oxygen) or S,
Y is O (oxygen), S or 1,4-piperazinylene,
Z is O (oxygen) or S,
m is a number from 1 to 3,
n is the number 0 or 1,
t is the number 0 or 1 and
u is the number 0 or 1,
and their salts.
Preferred embodiments of the invention are those of embodiments a to u, in which the substituents and symbols have the meanings of the preferred compounds according to the invention.
Exemplary compounds according to the invention are listed in the following tables:
If appropriate, it may be useful to introduce the radical xe2x80x94Xxe2x80x94Axe2x80x94[Yxe2x80x94CmH2m]txe2x80x94[Zxe2x80x94CnH2n]uxe2x80x94G completely or partially into the 4-position of the pyridine only after the reaction of an appropriately substituted 2-halomethylpyridine with the aminoquinoline II. The manner in which the compounds according to the invention can be obtained is shown in exemplary form in the following examples.
The compounds of the formula 11 are known or can be prepared in a known manner analogously to known compounds.
The compounds of the formula III are also known (see, for example, the abovementioned International Patent Applications in the section xe2x80x9cKnown Technical Backgroundxe2x80x9d) or the abovementioned complete or partial introduction of the radical xe2x80x94Xxe2x80x94Axe2x80x94[Yxe2x80x94CmH2m]txe2x80x94[Zxe2x80x94CnH2n]xe2x80x94G is described in the International Patent Applications mentioned.
The following examples explain the invention in greater detail without restricting it. The exemplary final products and the salts of these compounds are preferred subject matter of the invention. The compounds according to the invention and the starting compounds can be prepared in a manner analogous to that described in the examples. The abbreviation m.p. means melting point, conc. stands for xe2x80x9cconcentratedxe2x80x9d, h stands for hour(s).